Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is often a lethal complication of conventional genotoxic or cytotoxic cancer therapy. t-MDS/AML accounts for 15% of all AML and MDS cases and shares morphologic and cytogenetic characteristics with primary MDS and AML in the elderly. Lymphoma patients receiving conventional therapy are at an increased risk of developing t-MDS/AML, and this risk is considerably higher among patients receiving high-dose therapy with stem cell rescue. In particular, t-MDS/AML is a leading cause of non-relapse mortality following autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) (Bhatia et al. 1996, Miller et al. 1994; Pedersen-Bjergaard et al. 2000; Stone et al. 1994). The overwhelming majority of patients develop t-MDS/AML within 6 years after aHCT, and it has been shown that the cumulative probability of developing t-MDS/AML is about 8.6% within that time (FIG. 1).
In addition to exposure to conventional cancer therapies (e.g., chemotherapy and radiation therapy), it is thought that transplant conditioning, autograft collection and hematopoietic regeneration prior to aHCT also contribute to the development of t-MDS/AML (Bhatia et al. 1996; Kalaycio et al. 2006; Krishnan et al. 2000). However, its pathogenesis is not well understood and methods for predicting the risk of developing t-MDS/AML in individual cancer survivors are not available.
The study of t-MDS/AML provides an opportunity to understand leukemogenesis since genotoxic or cytotoxic exposures can be temporally and causally related to genetic changes associated with subsequent development of leukemia (Smith et al. 2003; Pedersen-Bjergaard 2005). Therefore, it is desired to identify changes in gene expression related to genetic changes that have an impact on the development of t-MDS/AML.